Our laboratory has proposed 10 years ago that there is a common endocrine control of bone mass, appetite and reproduction. We have in the last decade embarked in a two-pronged approach to verify this hypothesis. In the first aspect of our work we showed that the adipocyte - derived hormone leptin regulates bone mass via a central relay. In the second aspect of this work we then showed that the osteoblast-derived hormone osteocalcin favors glucose handling by the body and enhances energy homeostasis. Taken together, these two aspects of our work cover the first arm of our hypothesis namely that there is a common control of bone and energy metabolisms. More recently we came across another phenotype in the Osteocalcin-deficient mice that may allow us to establish an endocrine link between bone remodeling and reproduction. Indeed, Osteocalcin-deficient male mice are subfertile, have significantly smaller testes, decreased sperm counts and display a 60 to 80% decrease in circulating testosterone levels compared to wildtype littermates. These and additional preliminary data presented in this application suggest the hypothesis that osteocalcin may regulate not only energy metabolism but also reproduction. To further test this hypothesis we propose to use a combination of molecular, genetic and morphologic approaches. Our specific aims are: - To perform a thorough molecular and morphological characterization of the fertility phenotype of male Osteocalcin-deficient mice - To determine genetically and pharmacologically whether it is the carboxylated or the uncarboxylated form of osteocalcin that regulates spermatogenesis - To demonstrate genetically that it is through its osteoblast expression that osteocalcin favors sperm production and testosterone synthesis. - To use genetic epistasis to demonstrate that a putative osteocalcin receptor expressed on Leydig cells mediates osteocalcin function on sperm production and testosterone synthesis. PUBLIC HEALTH RELEVANCE: Osteocalcin-deficient male mice are subfertile, have decreased sperm counts and circulating testosterone levels compared to wildtype littermates suggesting that osteocalcin may regulate not only energy metabolism but also reproduction. To further test this hypothesis we propose to define the molecular bases of this phenotype and test which form of osteocalcin is involved in this novel function. We also intend to define which osteocalcin-producing cell type and whether a putative osteocalcin receptor is mediating osteocalcin regulation of male reproduction.